Group II metabotropic glutamate receptor (mGlu₂ and mGlu₃ ) roles in thalamic processing

As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu₂ /mGlu₃ ) receptor activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu₂ component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu₃ .

The somatosensory ventrobasal thalamus (VB) is an established model for probing fundamental principles of thalamic function. In vitro slices conserving VB-TRN circuitry from wild-type and mGlu₃ knockout mouse brains were used to record IPSPs and mIPSCs. In vivo extracellular recordings were made from VB neurons in anaesthetised rats. A range of selective pharmacological agents were used to probe Group II mGlu receptor function (agonist, LY354740; antagonist, LY341495; mGlu₂ positive allosteric modulator, LY487379 and mixed mGlu₂ agonist/mGlu₃ antagonist LY395756).

The in vitro and in vivo data are complementary and suggest that mGlu₃ receptor activation is largely responsible for potentiating responses to somatosensory stimulation by reducing inhibition from the TRN.

mGlu₃ receptor activation in the VB likely enables important somatosensory information to be discerned from background activity. These mGlu₃ receptors are likely to be endogenously activated via 'glutamate spillover'. In cognitive thalamic nuclei, this mechanism may be of importance in governing attentional processes. Positive allosteric modulation of endogenous mGlu₃ receptor activation may therefore enhance cognitive function in pathophysiological disease states, such as schizophrenia, thus representing a highly specific therapeutic target.

This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.